This proposal requests support for the sixth Gordon Research Conference on Three-dimensional Electron Microscopy of Macromolecules. In recent years, major advances have been made in the scope of electron microcopy as a powerful tool with unique capabilities for structural biology at the molecular level. Important technical breakthroughs have been made which enable three-dimensional structures to be determined with increasing accuracy, and which have opened the way to the study of macromolecular systems under defined physiological conditions. As a result, there are exciting new opportunities for understanding biological-mechanisms, interactions between macromolecules, and principles of molecular design. The unique position of this series of conferences derives from the fact that they help foster an integrated view of biological complexity, by bringing together scientists working on different levels of the structural hierarchy. These meetings serve to coalesce ideas concerning the preparation and visualization of biological specimens that range from the molecular to the subcellular. An emerging trend of major significance is the detection of large-scale conformational transitions in a wide range of macromolecules, a phenomenon that computer-assisted cryoelectron microscopy is uniquely positioned to investigate. Important progress has also been made in using electron microscopy to perform time-resolved studies of dynamic events. This year, for the first time, a major emphasis will be on four-dimensional electron microscopy. This conference will play a major role in shaping the further development of this field by bringing together many of the key investigators and allowing them to discuss their current work in a unique and informal setting. Speakers are being chosen on the basis of the importance of their recent contributions and the potential impact of their particular approach in future structure research. Topics to be covered include: regulatory conformational changes of macromolecules; time-resolved electron microscopy of kinetic precesses; conformational switches in membrane proteins and cytoskeletal filaments; electron crystallography; visualization of macromolecular interactions; advances in crystallization and electron optical instrumentation, including atomic force microscopy methods of three-dimensional image reconstruction and display; and recent results on a variety of macromolecular structures and methodological innovations.